POS1134 NOVEL APPROACH TO TREAT SYSTEMIC LUPUS ERYTHEMATOSUS, BY TARGETING THE “ROOT CAUSE”, B CELLS AND PLASMA CELLS, USING BCMA-CD19 COMPOUND CAR
Authors: Y. Yuan, S. He, W. Zhang, H. Zhang, V. Destefano, M. Wada, K. Pinz, G. Deener, Y. MA, M. Wang, F. LI, M. Hong, L. Ting, C. Zou, M. Wang, L. Ding, Y. Liang, Y. MA, W. Wang
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Systemic lupus erythematosus (SLE) is a heterogenous multi-system autoimmune disease characterized by presence of autoreactive antibodies produced by the "root" cause, B and plasma cells. Autoantibody depletion has been attempted by targeting B cells, however no such treatment addresses both B and plasma cells. <h3>Objectives</h3> We assess the safety and efficacy of dual resetting B and plasma cell populations using our novel BCMA-CD19 cCAR T (cCAR) in an open label phase I clinical trial. <h3>Methods</h3> We constructed a cCAR composed of a complete BCMA-CAR fused to a complete CD19-CAR, separated via self-cleaving P2A peptide. The cCAR functional activity was assessed in co-culture assays with multiple cell lines and mouse models. T cells from peripheral blood obtained via apheresis were transfected to create cCAR. Cessation of steroids and immunosuppressing medications was followed by conditioning. Patients received monthly IgG until B cells recovered. Patients were dosed from 1.5-3x10<sup>6</sup> cCAR cells/kg body weight and monitored. P1 and P2: 20-year history of managed SLE and received cCAR as compassionate use for B cell lymphoma. P1 and P2achieved complete remission (CR). After 1-year follow up demonstrated CR of SLE, hospital approved additional SLE/Lupus Nephritis (LN) patients for treatment. Baseline Characteristics: 12 patients received cCAR as of 15 Jan 2023. Patient age range: 20-58. Ten of 12 were female. P1 and P2: SLEDAI-2K score 4, and 8, respectively. Patient 3-12: SLEDAI-2K baseline score mean 11 range 6 to 16. All of patients (3-12) had LN on kidney biopsy between IV to V with failure of standard therapy. <h3>Results</h3> Safety: Overall cCAR has been well tolerated to date. There have been no severe adverse events (SAE) or infections attributed to cCAR, no CRES and no CRS above Grade 1. All patients with &gt;3 weeks follow up had a mild fever (CRS grade 1) which resolved with supportive care. Onset of mild fever occurred between days 3 to 14 and resolved within a week of onset. Efficacy: B cells were entirely depleted in peripheral blood 3-14 days post cCAR. Three patients treated &gt;6 months in CR (SLEDAI-2K = 0, all autoantibodies negative, and normal complement). P1 and P2 maintain drug free CR and with no autoantibodies post-cCAR approximately 40 and 20 months respectively. All B cells recovered within 2-6 months with no indications of relapse. At ≥1-4 months post-treatment 9 patients were negative for, anti-dsDNA autoantibody, anti-nuclear autoantibody, anti-SSA/Ro52 autoantibody, anti-SSA/Ro60 autoantibody, anti-ribosomal P, and anti-U1-snRNP. Among 9 patients rapid improvement within 1 month after cCAR, mean SLEDAI-2K dropped from 8.7 mean at baseline to 2 at 1 month (7 patients no symptoms), and mean drop to 0.88 within 6 months (9 patients no symptoms). All patients achieved 100% response and are maintaining medication free recovery (no immunosuppressives or glucocorticoids). An immune "reset" was confirmed via flow cytometry showing that most of recurring cells are naïve B cells, and further observed in BCR deep sequencing (patients 3-4), whereby IgG and IgA clonotypes are absent and non-class-switched BCR repertoires are greater than 95% IgM heavy chain. <h3>Conclusion</h3> These data on the 12 patients treated with cCAR demonstrate that the intervention is well tolerated. Initial data suggests immune system "reset" with long-term remission is possible as cCAR treats the "root cause" of disease by depleting autoreactive antibodies produced by plasma cells and memory B cells. This approach can be extended to other B and/or plasma cell mediated autoimmune disorders. The full dataset will be updated at the meeting. <h3>Acknowledgements</h3> Patients and their families. <h3>Disclosure of Interests</h3> Yong Yuan: None declared, Shanzhi He: None declared, Wenli Zhang: None declared, Hongyu Zhang: None declared, Vincent DeStefano Employee of: iCell Gene Therapeutics Inc., Masayuki Wada Employee of: iCell Gene Therapeutics Inc., Kevin Pinz Employee of: iCell Gene Therapeutics Inc., Greg Deener Employee of: Employee of iCell Gene Therapeutics Inc., Yu Ma Employee of: iCAR Bio Therapeutics Ltd, Min Wang: None declared, Fugui Li: None declared, Ming Hong: None declared, Lan Ting: None declared, Chanjuan Zou: None declared, Mingxia Wang: None declared, Ling Ding: None declared, Yingwen Liang: None declared, Yupo Ma Employee of: iCell Gene Therapeutics Inc., Weijia Wang: None declared.